There are a large number of therapeutic compounds that, due to poor water solubility, will not dissolve well in aqueous pharmaceutical carriers (making administration difficult) and exhibit poor availability. One solution has been to reformulate such drugs as water-soluble derivatives. This approach often yields compounds with less efficacy that the parent compound.
Another solution has been to incorporate hydrophobic drugs into micelles. Such micellar formulations are expected to achieve some level of circulation concentration of the drug without precipitation of the drug in the bloodstream. The principle behind micelle formation is that amphipathic molecules can form aggregates in an aqueous environment whereby hydrophobic components of the molecules come together to exclude water and make up the inner core of the micelle. The hydrophilic components of the molecules are orientated towards the outside of the micelle. This aggregation occurs above the critical micelle concentration (CMC) of the molecules in water. Under careful conditions, hydrophobic drugs may be solubilized in the inner hydrophobic core of micelles during their formation. These micellar formulations are utilized almost exclusively for the systemic administration of drugs and are usually delivered intravenously or intraperitoneally, but have also been suggested for oral administration.
The literature describes numerous methods to incorporate hydrophobic drugs such as methotrexate, indomethacin, paclitaxel and doxorubicin into micelles made from biocompatible, amphipathic polymeric molecules (e.g. U.S. Pat. No. 6,322,805; Kim S Y et al. J. Controlled Release (1998) 56:13-22; Inoue T et al. J. Controlled Release (1998) 51:221; and, Kataoka K I J Controlled Release (2000) 64:143-153). While the literature does describe formation of hydrophobic drug containing micelles with the hydrophobic drug and a micelle forming polymer being in aqueous solution during vigorous agitation or sonication of the solution, the amount of drug loading is poor as a result of its low solubility. Thus, micellar compositions are typically made by dissolving a hydrophobic drug in a water miscible organic solvent in which the drug is soluble, combining the resulting solution with a micellar composition in an aqueous solution with mixing by vigorous stirring, agitation, or sonication. For example, the mixture might be stirred for up to about 24 hours and any remaining drug not incorporated into micelles then removed. The resulting micellar solution may then be used directly for administration or freeze-dried into nanoparticles (which may be resuspended in water at a later time) providing the solvent is biocompatible and/or is capable of being removed by freeze-drying or other methods. These methods are complicated, expensive, and expose potentially water labile drugs to long periods in aqueous media. In addition there is a need to remove the organic solvent, which is often not pharmaceutically compatible or desirable.
One process for removal of an organic solvent is by solvent evaporation. In this method, a hydrophobic drug is typically dissolved in a water-miscible organic solvent and introduced to an aqueous solution of micelles. Subsequently, the organic solvent is evaporated off at elevated temperature. Alternatively, the drug and a micelle forming polymer are both dissolved in an organic solvent and the solvent is evaporated at elevated temperature. The resulting mixture is kept at an elevated temperature while warm water or aqueous solution is added with vigorous stirring until polymeric micelles containing the drug are formed. Also a dialysis method can be used, where a suitable water-miscible organic solvent is used to dissolve the hydrophobic drug and the micelle forming polymer. The solution is subsequently dialysed against a buffer solution and then against water. In some cases the duration of dialysis may be as long as 72 hours (Yu B. G. et al. J Controlled Release (1998) 56:285-291).
U.S. Pat. No. 4,745,160 (Churchill J. R. et al.) teaches a process for manufacturing micelle compositions from biodegradable amphipathic copolymers. The patent teaches that in order to incorporate a hydrophobic drug it is necessary to dissolve the drug in a water miscible organic solvent such as dioxan, acetic acid, acetonitrile, methanol or ethanol.
U.S. Pat. No. 5,510,103 (Yokoyama M. et al.) and U.S. Pat. No. 5,939,453 (Heller J. et al.) describe micelles made of block copolymers in which hydrophobic drugs are physically trapped. However, the disclosed methods of trapping require beating, ultrasonication, and/or the use of organic solvents and dialysis.
U.S. Pat. No. 6,136,846 (Rubinfeld J. et al.) describes incorporation of paclitaxel into micelles made from amphipathic block copolymers in which the hydrophobic block is a lipid tail. Organic solvents are used but the patent also teaches that polyethylene glycol (PEG) of 300-400 molecular weight may be used as the “solubilizer”. Paclitaxel loading of about 2% is reported in the examples set out in the patent.
Zhang X. et al. (Int'l. J. Pharmaceutics (1996) 132:195-206) reports the formation of a matrix containing taxol and a diblock copolymer composed of methoxy polyethylene glycol (MePEG) and polylactic acid. Only if the matrix is made with acetonitrile as an organic solvent, will the resulting matrix be capable of forming micelles following evaporation of the solvent. The resulting matrix must be heated to melt the polymer and vigorously agitated in aqueous medium in order to produce drug containing micelles.
In WO9921908, Zhang, X. et al., teaches the production of a semi-solid polymer mixture comprising hydrophobic drug, a water soluble polymer such as MePEG, and a hydrophobic polymer. It was found that the hydrophobic drug precipitates in the mixture thereby solidifying the material: